1.A.14.1.1
The Bax Inhibitor-1, BI-1 of 311 aas (or 237 aas; P55061) and 6 TMSs; it is also called the testis-enhanced gene transcript (TEGT) protein or the transmembrane BAX inhibitor motif-containing protein 6 (TMBIM6).  It forms an ER, pH-sensitive, cation-selective, Ca²⁺-permeable leak channel (Bultynck et al., 2011; Chang et al. 2014).  Residues that contribute to the ion-conducting pore and affect apoptosis, cell adhesion and migration independently have been identified (Carrara et al. 2015). The TMBIM6 calcium leak channel activity negatively regulates autophagy and autophagosome formation, influencing cardovascular traits (Swain et al. 2020). It enhances autophagy through regulation of lysosomal calcium (Kim et al. 2020). A TMBIM6 deficiency enhances susceptibility to ER stress due to inhibition of the ER stress sensor IRE1alpha. Its overexpression improves glucose metabolism, and knockout mice develop obesity (Philippaert et al. 2020). TMBIM6 knockout mice feature high glucose-stimulated insulin secretion in vivo. This coincides with profound changes in glucose-mediated Ca²⁺ regulation in isolated pancreatic beta cells and increases levels of IRE1alpha levels. TMBIM6-mediated metabolic alterations are mainly caused by its role as a Ca²⁺ release channel in the ER. Thus, TMBIM6(-/-) leads to obesity and hepatic steatosis by blocking Ca²⁺ transport (Philippaert et al. 2020). The mammalian Transmembrane BAX Inhibitor Motif (TMBIM) protein family in humans consists of six evolutionarily conserved hydrophobic proteins that affect programmed cell death and the regulation of intracellular calcium levels (Zhang et al. 2021). There are seven TMBIM family members in Drosophila melanogaster. Tmbim5 and 6 are essential for fly development and survival but affect cell survival through different mechanisms (Zhang et al. 2021). It prevents VDAC1 multimerization and improves mitochondrial quality control to reduce sepsis-related myocardial injury (Zhou et al. 2023).